New Haven, CONN. (6/9/98)- Simulating evolution in a
test-tube, Yale researchers have synthesized a DNA enzyme considered to
be key to understanding the origins of life on Earth some four billion
years ago.
The Yale
biologists have created a kind of DNA fossil, an unusual hybrid molecule
made up of a scaffold from deoxyribonucleic acid (DNA) with an RNA-destroying
enzyme attached to it. The synthesized enzyme is the first known nucleic
acid enzyme that uses an amino acid to trigger chemical activity, and represents
an important step towards understanding the origins of life on Earth.
Ronald R. Breaker and colleagues "looted the tool box of proteins" to
get the amino acid "scissors," which destroy messenger ribonucleic acid
(RNA) in humans and many other organisms. The feat was accomplished using
a technique known as test-tube evolution. In this case, the researchers
begin crafting an enzyme by synthesizing more than 10 trillion random DNA
sequences using a computerized DNA synthesizer. They then wash a grid containing
the sequences with various compounds, in this case histidine. Rare DNA
molecules that by chance fold into enzymes will break themselves free from
the grid. By cloning the DNA sequences that are washed away by the amino
acid and then repeating the process several times, the Yale biochemists
isolate desired enzymes.
"Our latest findings not only improve our understanding about the origins
of life, they also expand our skills in molecular evolution. While we may
not be able to resurrect fossilized creatures like they did in 'Jurassic
Park,' we very well may be able to recreate many of the ancient enzymes
that were needed at the very beginning of life nearly 4 billion years ago.
"If we can raid a protein's tool box to take one of its favored chemical
groups -- in this case, a key amino acid called histidine found in a protein called RNase A -- then we should
be able to raid the entire tool box and make use of anything we find there to make highly sophisticated DNA or RNA
enzymes," said Breaker.
Scientists investigating the origins of life run into a fundamental
question, which came first -- DNA, RNA or proteins? The prevailing "RNA World" hypothesis maintains that RNA
is the precursor of DNA. The hypothesis gained support with the discovery
nearly two decades ago of naturally occurring RNA enzymes, or ribozymes,
by Yale biochemist Sidney Altman and University of Colorado researcher
Thomas Cech, who won the 1989 Nobel Prize in Chemistry for their work.
Evidence is mounting that "it was an RNA World at the dawn of life as
the Earth began to cool," said Breaker, who added that he and his colleagues can create dual-purpose genetic
enzymes in the laboratory out of either RNA or DNA. "These genetic enzymes have the chemical sophistication,
the full catalytic ability, to do many of the fundamental reactions we see in biology today. I am confident one
will be created soon that can replicate itself."
While the Yale biologists created the versatile protein mimic from DNA,
Breaker theorizes that a similar enzyme could be created with RNA. In addition to RNA's dual function as genetic
molecule and as enzyme, RNA serves important roles as the carrier of genetic
instructions from DNA and as the orchestrator of all protein synthesis.
"This is exactly what you would expect if RNA invented these processes
during the 'RNA World. Because DNA is about a million times more stable
than RNA, DNA most likely evolved later as a safe storehouse for the genetic
code first found in RNA. Similarly, proteins probably evolved that were
more efficient chemical catalysts, eventually driving most RNA enzymes
extinct and relegating RNA to a more limited role," said Breaker.
The RNA World could have been a very sophisticated place. The earliest
RNA could have had access to all of these chemical helpers now used by
proteins. Instead of working from a very primitive palette, varieties of
RNA could have evolved that had a very rich chemical capability early on,
he noted.
In addition to contributing to the understanding of the origins of life,
research with ribozymes and DNA enzymes is expected to produce important
new genetically engineered antiviral compounds. Breaker and colleagues
have created self-cleaving DNA enzymes that can fold into chemically active
molecules and cut themselves or other DNAs into segments. The next step
is to genetically engineer a DNA enzyme that can shred the genetic
code of a harmful organism like the HIV virus, rendering it harmless.
Specific DNA enzymes also could be tailor-made to break down only in
the presence of target molecules, making them effective as biosensors for
detecting toxic chemicals in the environment or for medical diagnostics.
The research appears in the May 26, 1998 issue of the Proceedings of
the National Academy of Sciences.
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